Role of Bcl-2 Family Proteins in Photodynamic Therapy Mediated Cell Survival and Regulation

Abstract

Photodynamic therapy (PDT) is a treatment modality that involves three components: combination of a photosensitizer, light and molecular oxygen that leads to localized formation of reactive oxygen species (ROS). The ROS generated from this promising therapeutic modality can be lethal to the cell and leads to consequential destruction of tumor cells. However, sometimes the ROS trigger a stress response survival mechanism that helps the cells to cope with PDT-induced damage, resulting in resistance to the treatment. One preferred mechanism of cell death induced by PDT is apoptosis, and B-cell lymphoma 2 (Bcl-2) family proteins have been described as a major determinant of life or death decision of the death pathways. Apoptosis is a cellular self-destruction mechanism to remove old cells through the biological event of tissue homeostasis. The Bcl-2 family proteins act as a critical mediator of a life-death decision of cells in maintaining tissue homeostasis. There are several reports that show cancer cells developing resistance due to the increased interaction of the pro-survival Bcl-2 family proteins. However, the key mechanisms leading to apoptosis evasion and drug resistance have not been adequately understood. Therefore, it is critical to understand the mechanisms of PDT resistance, as well as the Bcl-2 family proteins, to give more insight into the treatment outcomes. In this review, we describe the role of Bcl-2 gene family proteins' interaction in response to disease progression and PDT-induced resistance mechanisms.

Keywords: Bcl-2 family; anti-apoptotic; cancer; cell survival; photodynamic therapy; pro-apoptotic.

Figure 1

The homology of Bcl-2 family proteins. There are three subfamilies of Bcl-2 proteins related by structure and function, with four different sequence homology regions, designated as BH1, BH2, BH3 and BH4. The BH3 region is common in all the subfamilies and participates in both anti- and pro-apoptotic activities. Non-Bcl-2 family proteins like Bag-1, Raf-1 and calcineurin also bind to the BH4 domain region.

Figure 2

Mechanism of photodynamic therapy (PDT). The toxic effect of reactive oxygen species molecules (hydroxyl radicals (OH⁻)), peroxides (H₂O₂) and superoxides (O₂⁻) produced via type I and type II (excited-state singlet oxygen (¹O₂)) photochemical processes that lead to phototoxicity and subsequent cell death via apoptosis, necrosis or autophagy.

Figure 3

The mitochondrial apoptotic pathway. The pathway is initiated through cellular stress or damaged signals that unleash the BH3-only activators through either bound to pro-survival or pro-apoptotic Bax/Bak proteins. The latter causes the mitochondrial membrane pore opening and leads to the mitochondrial outer membrane permeabilization (MOMP), resulting in the release of apoptogenic molecules and subsequent activation of caspases to initiate the cell death.